Project 3 builds upon extensive basic, translational and ongoing clinical work within DF/HCC, and addresses a clinically pressing issue: the need for more effective treatment strategies for sporadic triple negative breast cancer. It aims to shift current paradigms by the development of approaches that will sensitize BRCA-proficient triple negative breast cancer cells to PARP inhibition. Two highly innovative therapeutic strategies will be used, both involving newly appreciated aspects of homologous recombination. In Aim 1, we will focus on the development of a CDK inhibitor/PARP inhibitor combination utilizing dinaciclib and veliparib. The drug combination will be studied in triple negative breast cancer cell lines and orthotopic primary tumor xenograft models. Ultimately, the combination will be translated to a Phase 2 clinical trial that will explore efficacy and pharmacodynamic endpoints. Aim 2 takes advantage of another observation regarding previously unappreciated aspects of homologous recombination indicating that proteasome inhibition leads to a defect in homologous recombination, and thus sensitivity to PARP inhibition. We will proceed similarly through work in triple negative breast cancer cell lines, patient-derived orthotopic xenograft models and early phase clinical trial, focusing on the bortezomib/veliparib combination. For the clinical translation of the bortezomib/veliparib combination, the recommended phase 2 doses of the combination will be established in a UO1-supported phase 1 clinical trial. Following completion of the dose escalation, the SPORE will support enrollment of a triple negative breast cancer cohort in order to confirm safety in this population and to perform correlative studies.